Use of compositions for treating rosacea

ABSTRACT

Rosacea is treated with a composition comprising an antimicrobial and at least one of an anti-inflammatory and a non-retinoid inhibitor of at least one of NF- K B, AP-1, MMPs, adhesion molecules, TLRs, and CD14. The composition may further comprise a retinoid.

RELATED APPLICATIONS

This application is a division of Ser. No. 10/142,724, filed 9 May 2002,now U.S. Pat. No. ______, which is based on provisional application60/289,758, filed 9 May 2001, the disclosures of which are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention describes methods and compositions for ameliorating theeffects of rosacea, especially in combination with conventional therapy.

2. The State of the Art

Rosacea is a common facial dermatitis that currently affects anestimated 13 million Americans. It is a chronic and progressivecutaneous vascular disorder, primarily involving the malar and nasalareas of the face. Rosacea is characterized by flushing, erythema,papules, pustules, telanglectasia, facial edema, ocular lesions, and, inits most advanced and severe form, hyperplasia of tissue and sebaceousglands leading to rhinophyma. Rhinophyma, a florid overgrowth of the tipof the nose with hypervascularity and nodularity, is an unusualprogression of rosacea of unknown cause. Ocular lesions are common,including mild conjunctivitis, burning, and grittiness. Blepharitis, themost common ocular manifestation, is a nonulcerative condition of thelid margins.

Rosacea most commonly occurs between the ages of 30 to 60, and may beseen in women experiencing hormonal changes associated with menopause.Women are more frequently affected than men; the most severe cases,however, are seen in men. Fair complexioned individuals of NorthernEuropean descent are most likely to be at risk for rosacea; most appearto be pre-disposed to flushing and blushing.

Alcohol, stress, spicy foods, and extremes of temperature have all beenimplicated, but none have been found to actually cause rosacea. One ofthe most famous rosacea sufferers was W. C. Fields; his on-screenassociation with alcohol likely fostered the unsubstantiated associationbetween alcohol and rosacea. Although papules and pustules areassociated with rosacea, and hence its misnomer as “acne rosacea”, theoccurrence of P. acnes is generally not associated with the condition.

The cause of rosacea is poorly understood, numerous theories have beenoffered. Hypotheses have included gastrointestinal, psychological,infectious, climatic, and immunological causes, although scientificevidence has not substantiated any of these as primary. Controlledstudies have not demonstrated consistent preponderance ofgastrointestinal symptoms in rosacea patients. Similarly, neither adistinct psychological abnormality nor one pharmacological mechanism hasbeen isolated in rosacea patients. Perhaps the most commonly touted ofthe etiologic theories is based on the presence of Demodex folliculorummites in patients with rosacea; the organism feeds on sebum, and in somecases treatment of demodex infestation has noted improvement in therosacea; however, in a review of 79 biopsies in 1969, demodexfolliculorum was noted in only 19% of the specimens. A bacterial causefor the disease has been hypothesized, but no consistent findings of onebacteria have been demonstrated. Climate, specifically exposure toextremes of sun and cold, may have an effect on the course of thedisease, but the role of climate in what appears to be a connectivetissue disorder is not clear. An autoimmune process has been suggested,and tissue fixed immunoglobulins have been reported in patients withchronic inflammation of rosacea, but no other evidence has been found.Other experimental evidence has suggested this disease may represent atype of hypersensitivity reaction. No single hypothesis appears toadequately explain both the vascular changes and the inflammatoryreaction seen in rosacea, leaving the pathogenesis unclear. Morerecently, certain investigators have suggested a connection betweenrosacea and H. pylori, a bacteria shown to cause certaingastrointestinal ulcers, because symptoms seem to have abated in someulcer patients also suffering rosacea. Nevertheless, the connectionbetween H. pylori and rosacea has been questioned. H. Herr, J Korean MedSci October 2000; 15(5):551-4; R. Boni, Schweiz Med Wochenschr 16 Sep.2000; 130(37): 1305-8.

Histopathologic findings in rosacea dermatitis include vasculardilatation of the small vessels with perivascular infiltration ofhistiocytes, lymphocytes, and plasma cells. Dermal changes include lossof integrity of the superficial dermal connective tissue with edema,disruption of collagen fibers, and frequently severe elastosis.Follicular localization is infrequent and, when seen, is usuallymanifest clinically as pustules. However, there is no primary follicularabnormality. Rhinophyma is characterized histologically by an increasein sebaceous glands and connective tissue, follicular and vasculardilatation, edema, and a scattered infiltrate of perivascularlymphocytes and histiocytes. Immunoglobulin and compliment deposition atthe dermal epidermal junction have been reported in conjunctival andskin biopsies from rosacea patients. Ocular pathologic findings includeconjunctival and corneal infiltration with chronic inflammatory cells,including lymphocytes, epithelioid cells, plasma cells, and giant cells.

For the dermatological disease, the outcome of a successful managementregimen is usually control rather than eradication of the disease.Advising the patient to avoid those stimuli that tend to exacerbate thedisease—exposure to extremes of heat and cold, excessive sunlight,ingestion of hot liquids, alcohol, and spicy foods—may help. Althoughits mechanism of action is not clearly understood, the mainstay oftreatment is the use of oral tetracycline, especially for the papular orpustular lesions. The dosage utilized is generally 250 mg every 6 hoursfor the first 3 to 4 weeks, followed by tapering based on clinicalresponse. Doxycycline and minocycline (50-100 mg every 12 hours) arealso effective and have the advantage of less frequent dosage and lessconcern over problems with gastrointestinal absorption. Patients who areintolerant to the tetracyclines may benefit from the use oferythromycin. Oral isotretinoin, in doses similar to those used for acnevulgaris, has also been effective for the inflammatory lesions,erythema, and rhinophyma. There is, however, no beneficial effect on thetelangiectasias and isotretinoin may cause blepharitis andconjunctivitis. Other oral agents that have been used include ampicillinand metronidazole. Clonidine may also be of some value in reducingfacial flushing. Topical therapy for rosacea is generally lesssuccessful than systemic treatment, although often tried first.Metronidazole (2-methyl-5-nitroimidazole-1-ethanol) may be effectivetopically; it is available commercially as a 0.75% gel and, when appliedtwice daily, substantially reduces inflammatory lesions; it isclassified as an antiprotozoal. Although topical corticosteroids mayeffectively improve signs and symptoms, long-term therapy is notadvisable since it may cause atrophy, chronic vasodilation, andtelangiectasia formation. The treatment of chronic skin changes mayrequire surgical intervention. Telangiectasias may be treated byelectrocautery or using the tunable dye laser. Severerhinophyma istreated by paring with a scalpel, excision with skin grafting,dermabrasion, bipolar electrocautery, or by means of the argon or carbondioxide laser.

The typical course of treatment is to start with metronidazole, and ifthat is not as effective as desired to ameliorate the symptoms, or thecondition worsens, then therapy is switched to a stronger antimicrobial,such as tetracycline or minocycline. This standard course of therapypersists under the pretense that the antimicrobial is reducinginflammation, because inflammation appears to be reduced, even though itis logically the antimicrobial effects that cause the reduction ininflammation (and because these types of compounds are not known to haveantiinflammatory properties).

In 1990, Akamatsu et al. (“The inhibition of free radical generation byhuman neutrophils through the synergistic effects of metronidazole withpalmitoleic acid: a possible mechanism of action of metronidazole inrosacea and acne,” Arch Dermatol Res 1990; 282(7):449-54) described thesynergistic effects of metronidazole and palmitoleic acid on theanaerobic growth of P. acnes as well as on human neutrophil functions,including the generation of reactive oxygen species (ROS). Bothmetronidazole and palmitoleic acid, when used alone, only slightlyinhibited the growth of P. acnes, and no significant decrease in humanneutrophil functions, including the generation of ROS, was observed; butmetronidazole used in the presence of palmitoleic acid (naturallypresent in human skin) markedly inhibited the anaerobic growth of P.acnes and decreased ROS generation by neutrophils. They conclude that byinhibiting oxidative tissue injury under in vivo conditions, treatmentwith metronidazole results in remarkable improvement of rosacea andacne.

U.S. Pat. No. 6,228,887 to Kligman discloses treating such skindisorders as photodamage, hyperpigmentation, rosacea, and scarringtopically with high strength retinoids at a concentration effective tocause desquamation. Retinoids activate the the epidermal growth factorreceptor, causing hyperproliferation of skin cells, which results in thedesquamation sought by this patent. The clinical examples given in thispatent only involve treating photodamaged skin.

SUMMARY AND OBJECTS OF THE INVENTION

The primary object of this invention is to supplement the treatment ofrosacea by addressing the inflammatory and collagen-degrading componentsof the condition, through preferably topical administration of one ormore compounds.

Thus, in one respect, this invention provides a method for treatingrosacea that comprises administering to a patient in need thereof (i) anantimicrobial and (ii) at least one of (a) an anti-inflammatory and (b)a non-retinoid inhibitor of at least one AP-1, NF-KB, MMP, and TLR. In apreferred embodiment, the composition also includes a retinoid, whichtypically acts to inhibit AP-1, NF-KB, and various MMPs, although someretinoids may inhibit fewer than all of these. Most preferably, theanti-inflammatory and/or the non-retinoid inhibitor is administeredtopically.

In another respect, this invention provides a topical composition fortreating rosacea which comprises a combination of an antimicrobial andat least one of (a) an anti-inflammatory and (b) a non-retinoidinhibitor of at least one AP-1, NF-KB, MMP, and TLR.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

While likely distinct, the present invention may be better understoodwith respect to the present inventors' findings in the treatment ofacne. Acne is a multifactorial disease, developing in the sebaceousfollicles. At least one agent thought responsible is the anaerobePropionibacterium acnes (P. acnes); in younger individuals, practicallyno P. acnes is found in the follicles of those without acne. In general,there are four major principles presently governing the therapy of acne:(i) correction of the altered pattern of follicular keratinization; (ii)decrease sebaceous gland activity; (iii) decrease the follicularbacterial population (especially P. acnes) and inhibit the production ofextracellular inflammatory products through the inhibition of thesemicroorganisms; and (iv) produce an anti-inflammatory effect. Thepresent treatments for acne following these principals typicallyinclude: vitamin A acid (retinoic acid), known for its comedolyticproperties, administered topically (e.g., Retin-A® brand 0.025%all-trans retinoic acid cream) or systemically (e.g., Accutane® brand13-cis retinoic acid); an antibiotic administered systemically (e.g.,tetracycline or one of its derivatives) or topically (e.g., benzoylperoxide, erythromycin, clindamycin, azelaic acid); the use of othercomedolytic agents such as salicylic acid; or the use of systemicanti-androgens such as cyproterone acetate and spironolactone (becauseandrogens promote sebum production, and sebum has been found to becomedogenic and inflammatory), which may be administered in combinationwith an estrogen.

The art has addressed inflammation and scarring caused by acne as asecondary benefit to the treatment of the disease; that is, if the acneis cured the factors causing scarring will be eliminated. There isotherwise no treatment directed at preventing scarring from acne.Neither is there presently any direct treatment for the inflammationaccompanying acne. The conventional treatment acts to prevent furtherproblems by alleviating the cause of the acne; for example, a patient istreated with tetracycline, an antiobiotic, in hopes of killing the P.acnes, and the death of the bacteria will effectively end theinflammation and future scarring. Much as antipyretics, analgesics,decongestants, and antihistamines have been developed to treat thesymptoms of colds and upper respiratory infections (as opposed toantibiotics and antivirals to kill off the invading bacteria andviruses), there is a need for treatments diminishing if not preventingscarring and inflammation in acne.

In connection with acne, we have discovered that neutrophils (PMNs),immune cells that migrate to areas of injury, invade acne-affected skin,and release both a collagenase (MMP-8) and another protease (neutrophilelastase) that likely exacerbate scarring. Additionally, we havediscovered that acne-affected skin has an elevated collagenase (MMP-1)level from resident skin cells that further exacerbates scarring. Wehave disclosed that inhibition of these dermal matrix-degrading enzymeswith the use of MMP inhibitors (in addition to and including retinoids)can lessen scarring of acne-affected skin. Neutrophils circulate in theblood and therfore must be recruited by a signalling mechanism to inducetheir presence in the skin, facilitate their infiltration to theaffected site, and enable their release of MMP-8 and elastase.Accordingly, impeding or disrupting the signalling which induces theirpresence in the skin and/or the activity of MMP-8 or elastase is likelyto diminish the accompanying inflammation and the degradatory action ofMMP-8 and/or elastase.

Although rosacea is not believed to be cause by P. acnes, theconventional wisdom is that rosacea is caused or exacerbated by demodexmites which live in human hair follicles. The present inventors believethat these microbes cause an inflammatory reaction, analogous to theinflammation described in connection with inflammation in acne. It isbelieved that the inflammatory agent is excretia from the mites, aprotein shed by the mite, a CD-14 binding protein carried by the mitethat activates a TLR (toll-like receptor), or some combination thereof,and the inflammatory reaction is believed to involve AP-1, NF-KB, andthe subsequent production of MMPs in the skin.

Accordingly, a treatment that inhibits TLR activation of NF-KB and/orthat inhibits induction of polymorphonuclear lukocytes would likely aidin the treatment of rosacea. Activation of the TLRs causes NF-KB toenter the cell nucleus of keratinocyes. The keratinocytes are thusinduced to release chemotactic factors, especially cytokines (IL-1β,IL-8, IL-10, TNFα). These factors activate the AP-1 and NF-KB pathways,and NF-KB activates more IL-1 and TNFα (a cyclical process, such as inFIG. 1 of U.S. Pat. No. 5,837,224 on photoaging due to UV radiation).The release of these factors causes inflammation, including therecruitment of neutrophils (PMNs; i.e., polymorphonuclear leukocytes)from the blood supply to the area from which the signallying was sent;MMP-8 and elastase are preformed in the neutrophils and so when theneutrophils arrive at the site of the rosacea, these dermalmatrix-degrading enzymes arrive at the area. The cytokines also effectother keratinocytes and fibroblasts (FB), which are resident in theskin, to generate MMPs.

CD-14 is a “pattern recognition” protein that is a part of the innateimmune response in humans. It binds to LPS-like substances, such as areproduced by P. acnes. When the bound CD-14 encounters a toll-likereceptor (TLR), it binds to it and thereby activates it. It is believed(without being constrained thereto) that a compound (likely a protein)produced, excreted, or otherwise shed by demodex likely binds to CD14proteins. These bound proteins then activate TLRs, which causes orexacerbates the inflammation in rosacea. Alternatively, the demodex mayhave on its surface compounds that bind to CD14, such that the boundcomplex breaks off from the mite, or the mite otherwise transfers thecomplex to the TLR, which causes the inflammatory reaction.

This inflammatory response can directly induce MMPs. The NF-KB from theTLR causes cells to produce inflammatory cytokines, such as TNFα, IL-1β,IL-8, and/or IL-10. TNFα and IL-1β, acting through NF-KB, can inducekeratinocytes and fibroblasts to produce MMPs. On the other front, IL-8and IL-10 induce chemotaxis and adhesion molecules to recruite PMNs fromthe blood stream; these cells have their own supply of MMP-8 andelastase, and so bring these matrix degrading enzymes to the site ofinflammation, namely rosacea. This mechanism would appear to befacilitated by the hypervascularity associated with rosacea, providing awell-infused site and thus hyper-recruitement of PMNs because of theincreased vascularity at the affected site.

It might seem counter-intuitive that MMP induction could result inhyperplasia leading to rhinophyma. In this regard, fibroblasts aresensitive to the matrix around them: when in contact with an intactmatrix, they tend to be less active and to produce little collagen; whenin the presence of gelatin (collagen breakdown products), then tend toproduce more collagen to repair the matrix. There may likely be a cyclewhereby some factor (such as bacteria or the demodex mites) causesinflammation that induces MMPs, and the collage breakdown productsinduces collagen production and hyperplasia; as the cause ofinflammation persists and so the breakdown products are constantly beingformed, the fibroblasts are prompted to proliferate and produce morecollagen, and those newly proliferated fibroblasts will also be promptedto proliferate and produce more collagen.

Accordingly, it is likely important to break this cycle at multiplepoints. Thus, in combination with existing antimicrobial or isotretinointherapy, this invention adds an anti-inflammatory therapy. The presenttherapy includes as an adjunct to oral isotretinoin therapy orantimicrobial therapy an inhibitor of NF-KB, AP-1, and/or of MMPs.Alternatively, as an adjunct to antimicrobial therapy, this inventionprovides the use of a topical retinoid, which inhibits NF-KB and AP-1induction of MMPs, as well as inhibiting JNK induction of MMPs.

Aspirin and E5510 (described by Fujimori, T., et at., Jpn J Pharmacol(1991) 55(I):81-91) inhibit NF-KB activation. Farnesyl transferaseinhibitors such as B-581 (described by Garcia A. M., et al., J Biol Chem(1993) 268(25):18415-18), BZA-5B (described by Dalton M. B. et al.,Cancer Res (1995) 55(15):3295-3304), farnesyl acetate, and(α-hydroxyfarnesyl) phosphoric acid act on RAS and thus inhibitactivation of the resultant ERK cascade; ERK leads to c-fos, whichheterodimerizes with c-jun to create AP-1. Other useful inhibitors arethose that inhibit NF-KB, such as sulfasalazine and parthenolide, serineprotease (elastase) inhibitors, and antiadhesion molecules such asneutrophil infiltration inhibitors (e.g., selectin antagonists).

As used herein, “inhibitors” of MMPs and other dermal matrix-degradingenzymes, such as elastase, inhibit one or more of the steps in thenatural physiological pathways leading to the production of theseenzymes and/or directly inhibit one or more of these proteases, or theydirectly inhibit the activity of the enzyme. Thus, as used herein an“inhibitor” excludes retinoids, inasmuch as retinoids and tetracyclineshave been known for treating acne, this invention is directed to thenovel use of a non-retinoid enzyme inhibitor, which use may be combinedwith the conventional use of a retinoid and/or a tetracycline. Thus, an“inhibitor” is a non-retinoid compound that directly inhibits one ormore dermal matrix-degrading enzymes and/or indirectly inhibits theenzyme by inhibiting some portion of an upstream pathway(s) leading toone or more of these dermal matrix-degrading enzymes. Inhibition of theupstream pathway of these dermal matrix-degrading enzymes includesinhibition of one or more of the various signalling compounds and/or ofthe transcription factors (e.g., NF-KB, or cJUN and cFOS which togethercreate AP-1) by which these enzymes are produced naturally.

MMPs are also inhibited by BB2284 (described by Gearing, A. J. H. etal., Nature (1994) 370:555-557), GI129471 (described by McGeehan G. M.,et al., Nature (1994) 370:558-561), and TIMPs (tissue inhibitors ofmetalloproteinases, which inhibit vertebrate collagenases and othermetalloproteases, including gelatinase and stromelysin). Other compoundsuseful for the present invention are direct MMP inhibitors such ashydroxamate and hydroxy-urea derivatives, the latter exemplified byGalardin, Batimastat, and Marimastat, and those disclosed in thetreatment of, among other etiologies, skin ulcers, skin cancer, andepidermolysis bullosa).

Indirect MMP inhibitors include the kinase inhibitors genistein andquercetin (as described in U.S. Pat. No. 5,637,703, U.S. Pat. No.5,665,367, and FR-A-2,671,724, and related compounds, as well as otherantioxidants such as NAC (N-acetyl cysteine), discussed below. Stillfurther, other kinase inhibitors such as SB202190 (described by Lee, J.C., et al., Nature (1994) 372:739-746) and PD98059 (described by Dudley,D. T., et al., PNAS (USA) (1995) 92:7686-7689) inhibit specific kinasesin the cascades, geranyl geranyltransferase inhibitors and lisofylline,which inhibit activation of the JNK cascade resulting from RAC/CDC42activation, and U0126(1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene). As notedabove, compounds that inhibit cytokines are indirect MMP inhibitorsbecause interrupting the signalling pathway effectively inhibits MMPs.MMPs are also inhibited by BB2284 (described by Gearing, A. J. H. etal., Nature (1994) 370:555-557), GI129471 (described by McGeehan G. M.,et al., Nature (1994) 370:558-561), and TIMPs (tissue inhibitors ofmetalloproteinases, which inhibit vertebrate collagenases and othermetalloproteases, including gelatinase and stromelysin). Still othercompounds useful for the present invention include hydroxamate andhydroxy-urea derivatives which are direct MMP inhibitors, and which areexemplified by such compounds as Galardin, Batimastat, and Marimastat,and those disclosed in EP-A1-0 558635 and EP-A1-0 558648 (as useful forinhibiting MMPs in the treatment of, among other etiologies, skinulcers, skin cancer, and epidermolysis bullosa).

Inhibitors of activator protein-1 (AP-1) are likely to inhibit thesubsequent signalling that results in the presence of MMPs in the dermalmatrix; the more of the pathway that is inhibited, the more likely therewill be no induction of MMPs. Among various compounds that have beenfound to inhibit AP-1 and may likely be used topically include thefollowing. Cannabinoids: Faubert and Kaminski; “AP-1 activity isnegatively regulated by cannabinol through inhibition of its proteincomponents, c-fos and c-jun”, J Leukoc Biol, vol. 67, no. 2 (February2000, pp. 259-66) (Cannabinoid compounds exhibit immunosuppressiveactions that are putatively mediated through Gi-protein coupledreceptors that negatively regulate adenylate cyclase. However, recentstudies suggest that cannabinoids modulate other signaling cascades.Cannabinol inhibited binding to AP-1-containing sites from theinterleukin-2 promoter, in part, due to decreased nuclear expression ofc-fos and c-jun. Thus, cannabinoid-induced immunosuppression involvesdisruption of the ERK signaling cascade.) Deferroxamine (DFO);Kramer-Stickland et al., “Inhibitory effects of deferoxamine onUVB-induced AP-1 transactivation”, Carcinogenesis, vol. 20, no. 11,November 1999, pp. 2137-42 (Production of reactive oxygen species (ROS)by iron can contribute directly to DNA and protein damage and maycontribute to cell signaling and proliferation. DFO treatment 24 h priorto UVB irradiation reduced UVB-induced AP-1 transactivation byapproximately 80%, with the effect of DFO diminishing as pre-treatmenttime was shortened. Treatment with FeCl(3) a minimum of 6 h prior to UVBpotentiated the UVB induction of AP-1 transactivation by 2-3-fold.)Separately, gadolinium chloride and alpha-tocopherol: Camandola et al.,“Liver AP-1 activation due to carbon tetrachloride is potentiated by1,2-dibromoethane but is inhibited by alpha-tocopherol or gadoliniumchloride”, Free Radic Biol Med, vol. 26, no. 9-10, May 1999, pp.1108-16. Cyclosporin A: Sugano et al., “Cyclosporin A inhibitscollagenase gene expression via AP-1 and JNK suppression in humangingival fibroblasts, J Periodontal Res, vol. 33, no. 8, November 1998,pp. 448-452 (Cyclosporin A is able to affect signal transduction oflipidpolysaccharide-induced collagenase expression in fibroblasts;treatment of fibroblasts with LPS caused activation of collagenase gene,activator protein-1 (AP-1) and c-Jun N-terminal kinase (JNK). Theseactivations were blocked by CsA. They suggest that inhibitory effects ofCsA on LPS-induced signal transduction may contribute to the mechanismof CsA-induced gingival overgrowth. Catachins: Barthelman et al.,“(−)-Epigallocatechin-3-gallate inhibition of ultraviolet B-induced AP-1activity”, Carcinogenesis, vol. 19, no. 12, December 1998, pp. 2201-4(using cultured human keratinocytes, UVB-induced AP-1 activity isinhibited by EGCG in a dose range of 5.45 nM to 54.5 microM; EGCG iseffective at inhibiting AP-1 activity when applied before, after or bothbefore and after UVB irradiation; EGCG also inhibits AP-1 activity inthe epidermis of a transgenic mouse model). Naphthopyranomycins andexfoliamycins, such as K1115 A (Naruse et al., “K115A, , a newanthraquinone that inhibits the binding of activator protein-1 (AP-1) toits recognition sites II. Taxonomy, fermentation, isolation,physico-chemical properties and structure determination,” J Antibiot(Tokyo), vol 51, no. 6, June 1998, pp. 545-52; the anthraquinone3,8-dihydroxy-1-propylanthraquinone-2-carboxylic acid). DHEA: Dashtakiet al., “Dehydroepiandrosterone and analogs inhibit DNA binding of AP-1and airway smooth muscle proliferation”, J Pharmacol Exp Ther, vol. 285,no. 2, May 1998 (pp. 876-83) (dehydroepiandrosterone (DHEA) and itsanalogs such as 16-alpha-bromoepiandrosterone). Oleanolic acidglycosides: Lee et al., “Momordins inhibit both AP-1 function and cellproliferation,” Anticancer Res, vol. 18, no. 1A, January-February 1999(pp. 119-24). Monoterpene perillyl alcohol: Barthelman et al.,“Inhibitory effects of perillyl alcohol on UVB-induced murine skincancer and AP-1 transactivation”, Cancer Res., vol. 58, no. 4, 15 Feb.1998 (pp. 711-6). Curcumin, which inhibits both AP-1 and NF-KB: Xu etal., “Curcumin inhibits IL1 alpha and TNF-alpha induction of AP-1 andNF-kB DNA-binding activity in bone marrow stromal cells,” HematopatholMol Hematol, vol. 11, no. 1, 1997-8 (pp. 49-62); and Pendurthi et al.,“Suppression of activation of transcription factors Egr-1, AP-1, andNF-kappa B,” Arterioscler Thromb Vasc Biol, vol. 17, no. 12, December1997 (pp. 3406-13); and Bierhaus et al., “The dietary pigment curcuminreduces endothelial tissue factor gene expression by inhibiting bindingof AP-1 to the DNA and activation of NF-kappa B,” Thromb Haemost, vol.77, no. 4, April 1997 (pp. 772-82). Aspirin (acetylsalicylic acid):Huang et al., “Inhibition of ultraviolet B-induced activator protein-1(AP-1) activity by aspirin in AP-1-luciferase transgenic mice”, J BiolChem, vol. 272, no. 42, 17 Oct. 1997 (pp. 26325-31). Pyrrolidinedithiocarbamate and N-acetyl cysteine (inhibit AP-1, NF-KB, and IL-8):Munoz et al., “Pyrrolidine dithiocarbamate inhibits the production ofinterleukin-6, interleukin-8, and granulocyte-macrophagecolony-stimulating factor by human endothelial cells in response toinflammatory mediators: modulation of NF-kappa B and AP-1 transcriptionfactors activity”, Blood, vol. 88, no. 9, 1 Nov. 1996 (pp. 3482-90).Metal salts, such as gold (I) and selenite: Handel et al., “Inhibitionof AP-1 binding and transcription by gold and selenium involvingconserved cysteine residues in Jun and Fos,” Proc Natl Acad Sci USA,vol. 92, no. 10, 9 May 1995 (pp. 4497-501) (in electrophoreticmobility-shift analyses, AP-1 DNA binding was inhibited by gold(l)thiolates and selenite, with 50% inhibition occurring at approximately 5microM and 1 microM, respectively; and other metal ions inhibited athigher concentrations, in a rank order correlating with their thiolbinding affinities); and Spyrou et al, “AP-1 DNA-binding activity isinhibited by selenite and selenodiglutathione”, FEBS Lett, vol. 368, no.1, 10 Jul. 1995 (pp. 59-63) (selenite and selenodiglutathione(GS-Se-SG)); and Williams et al., “Aurothioglucose inhibits inducedNF-kB and AP-1 activity by acting as an IL-1 functional antagonist”,Biochim Biophys Acta, vol. 1180, no. 1, 13 Oct. 1992 (pp. 9-14).

NF-KB inhibitors include those disclosed in the following references.Cyclopentenone prostaglandins: Rossi et al., “Anti-inflammatorycyclopentenone prostaglandins are direct inhibitors of IkappaB kinase”,Nature, vol. 403, no. 6765, 6 Jan. 2000 (pp. 103-8). Quercetin andstaurosporine: Peet and Li, “IkappaB kinases alpha and beta show arandom sequential kinetic mechanism and are inhibited by staurosporineand quercetin”, J Biol Chem, vol. 274, no. 46, 12 Nov. 1999 (pp.32655-61) (but not the quercetin analogue Daidzein). Nepalolide A: Wanget al., “Nepalolide A inhibits the expression of inducible nitric oxidesynthase by modulating the degradation of IkappaB-alpha and IkappaB-betain C6 glioma cells and rat primary astrocytes”, Br J Pharmacol, vol.128, no. 2, September 1999 (pp. 345-56). Turmeric (curcumin): Plummer etal., “Inhibition of cyclo-oxygenase 2 expression in colon cells by thechemopreventive agent curcumin involves inhibition of NF-kappaBactivation via the NIK/IKK signalling complex”, Oncogene, vol. 18, no.44, 28 Oct. 1999 (pp. 6013-20). Salicylates: Stevenson et al.,“Salicylic acid and aspirin inhibit the activity of RSK2 kinase andrepress RSK2-dependent transcription of cyclic AMP response elementbinding protein- and NF-kappa B-responsive genes”, J Immunol, vol. 163,no. 10, 15 Nov. 1999 (pp. 5608-16). Diterpenes: de las Heras et al.,“Inhibition of NOS-2 expression in macrophages through the inactivationof NF-kappaB by andalusol”, Br J Pharmacol, vol. 128, no. 3, October1999 (pp. 605-12) (andalusol, ent-6α,8α,18-trihydroxy-13(16),14-labdadiene, is a naturally occurring diterpene,isolated from Sideritis foetens (Lamiaceae). N-substituted benzamides:Liberg et al., “N-substituted benzamides inhibit NFkappaB activation andinduce apoptosis by separate mechanisms”, Br J Cancer, vol. 81, no. 6,November 1999 (pp. 981-8). While not preferred due to potential toxicityissues, arsenic: Estrov et al., “Phenylarsine oxide blocksinterleukin-1β-induced activation of the nuclear transcription factorNF-KB, inhibits proliferation, and induces apoptosis of acutemyelogenous leukemia cells”, Blood, vol. 94, no. 8, 15 Oct. 1999 (pp.2844-53). Genistein: Tabary et al., “Genistein inhibits constitutive andinducible NFkappaB activation and decreases IL-8 production by humancystic fibrosis bronchial gland cells”, Am J Pathol, vol. 155, no. 2,August 1999 (pp. 473-81). Theophylline: Tomita et al., “Functional assayof NF-kappaB translocation into nuclei by laser scanning cytometry:inhibitory effect by dexamethasone or theophylline”, NaunynSchmiedebergs Arch Pharmacol, vol. 359, no. 4, April 1999 (pp. 249-55).Cepharanthine: a plant alkaloid (I) (Merck Index 11, 306, 1981), anddescribed in U.S. Pat. Nos. 2,206,407 and 2,248,241, and JapanesePatents 120,483, 128,533, and 141,292. Trifluoroalkyl salicylates: Bayonet al., “4-trifluoromethyl derivatives of salicylate, triflusal and itsmain metabolite 2-hydroxy-4-trifluoromethylbenzoic acid, are potentinhibitors of nuclear factor kappaB activation”, Br J Pharmacol, vol.126, no. 6, March 1999 (pp. 1359-66) (2-hydroxy-4-trifluoromethylbenzoicacid (HTB) and 2-acetoxy-4-trifluoromethylbenzoic acid (triflusal), bothmore potent than aspirin or salicylate as inhibitors of NF-KB,indicating that the incorporation of a 4-trifluoromethyl group to thesalicylate molecule strongly enhances its inhibitory effect on NF-KBactivation). Quinapril: quinapril hydrochloride is chemically describedas[3S-[2[R*(R*)],3R*]]-2-[2-[[1-(ethoxycarbonyl)-3-phenylpropyl]amino]-1-oxopropyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylicacid, monohydrochloride. Its empirical formula is C₂₅H₃₀N₂O₅.HCl.Cyclosporine A: Meyer et al, “Cyclosporine A is an uncompetitiveinhibitor of proteasome activity and prevents NF-kappaB activation”,FEBS Lett, vol. 413, no. 2, 18 Aug. 1997 (pp. 354-8). Arachidonic acidderivatives: Thommensen et al., “Selective inhibitors of cytosolic orsecretory phospholipase A2 block TNF-induced activation of transcriptionfactor nuclear factor-kappa B and expression of ICAM-1”, J Immunol, vol.161, no. 7, 1 Oct. 1998 (pp. 3421-30) (TNF-induced activation of NF-KBinhibited by trifluoromethyl ketone analogue of arachidonic acid(AACOCF₃), methyl arachidonyl fluorophosphate, trifluoromethyl ketoneanalogue of eicosapentaenoic acid (EPACOCF₃), 12-epi-scalaradial, andLY311727; arachidonyl methyl ketone analogue (AACOCH₃) and theeicosapentanoyl analogue (EPACHOHCF₃) had no effect on TNF-induced NF-KBactivation. Genistein, erbstatin: Natarajan et al., “Protein tyrosinekinase inhibitors block tumor necrosis factor-induced activation ofnuclear factor-KB, degradation of IKBα, nuclear translocation of p65,and subsequent gene expression”, Arch Biochem Biophys, vol. 352, no. 1,1 Apr. 1998 (pp. 59-70). Fasudil:1-(5-isoquinolinesulfonyl)homopiperazine hydrochloride (fasudilhydrochloride); Sato et al., “Inhibition of human immunodeficiency virustype 1 replication by a bioavailable serine/threonine kinase inhibitor,fasudil hydrochloride”, AIDS Res Hum Retroviruses, vol. 14, no. 4, 1Mar. 1998 (pp. 293-8). ACE (angiotensin converting enzyme) inhibitors,like quinipril: Hernandez-Presa et al., “Angiotensin-converting enzymeinhibition prevents arterial nuclear factor-kappa B activation, monocytechemoattractant protein-1 expression, and macrophage infiltration in arabbit model of early accelerated atherosclerosis”, Circulation, vol.95, no. 6, 18 Mar. 1997 (pp. 1532-41). Synthetic 1,3,7-trialkyl xanthinederivatives, such as pentoxifylline(3,7-dimethyl-1-(5-oxohexyl)xanthine; Drugs & Aging 1995, 7/6: 480-503)and denbufylline (1,3-dibutyl-7-(2-oxopropyl)xanthine); Lee et al.,“Pentoxifylline blocks hepatic stellate cell activation independently ofphosphodiesterase inhibitory activity”, Am J Physiol, vol. 273, no. 5 Pt1, November 1997 (pp. G1094-100). Benzophenanthradine derivatives:Chaturvedi et al., “Sanguinarine (pseudochelerythrine) is a potentinhibitor of NF-KB activation, IKBα phosphorylation, and degradation”, JBiol Chem, vol. 272, no. 48, 28 Nov. 1997 (pp. 30129-34) (sanguinarine,a benzophenanthridine alkaloid). Actinomycin D: Faggioli et al.,“Protein synthesis inhibitors cycloheximide and anisomycin induceinterleukin-6 gene expression and activate transcription factor NF-KB”,Biochem Biophys Res Commun, vol. 233, no. 2, 17 Apr. 1997 (pp. 507-13)(IL-6 mRNA accumulation in two human cell lines, MDA-MB-231 and HeLa,stimulated by cycloheximide or anisomycin is almost completely inhibitedin the presence of actinomycin D). Hydroxyanthranilic acids: Sekkai etal., “Inhibition of nitric oxide synthase expression and activity inmacrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite”, ArchBiochem Biophys, vol. 340, no. 1, 1 Apr. 1997 (pp. 117-23)(3-hydroxyanthranilic acid but not anthranilic acid).Nordihydroguaiaretic acid and AA861: Lee et al., “Inhibition of5-lipoxygenase blocks IL-1 beta-induced vascular adhesion molecule-1gene expression in human endothelial cells”, J Immunol, vol. 158, no. 7,1 Apr. 1997 (pp. 3401-7). Prostaglandin A1: Rossi et al., “Inhibition ofnuclear factor kappa B by prostaglandin A1: an effect associated withheat shock transcription factor activation”, Proc Natl Acad Sci USA,vol. 94, no. 2, 21 Jan. 1997 (pp. 746-50).

Sialyl Lewis X (SLe.sup.x) mediates binding of neutrophils to vascularendothelial cells by binding to E-selectin. (M. Phillips, et al.,Science 1990, 250, 1130.; J. Lowe, et al., Cell 1990, 63, 475; T. Feizi,Trends Biochem Sci 1991, 16, 84; M. Tiemeyer., et al., Proc. Natl. Acad.Sci. USA 1991, 88, 1138; L. Lasky, Science 1992, 258, 964; and T.Springer, L. A. Lasky, Nature 1991, 349, 196.) Sialyl Lewis X(SLe.sup.x) is a cell surface carbohydrate ligand found on neutrophils,anchored onto the outer membrane thereof by integral membraneglycoproteins and/or glycolipids. Administration of SLe.sup.x inhibitsthe SLe.sup.x/E-selectin interaction and blocks adhesion of neutophilsto endothelial cells. (M. Buerke, et al., J. Clin. Invest., 1994,1140.). Neutrophil-mediated inflammatory diseases may be treated byadministration of Sialyl Lewis X (SLe.sup.x). Selectin inhibitor includethose in the following references. E-, P-, and L-selectin inhibitors inU.S. Pat. No. 5,830,871. Sulfatides and sialylated or sulfatedfucooligosaccharides, as described in U.S. Pat. No. 5,985,852, and otherfucose derivatives as described in U.S. Pat. No. 5,962,422 and U.S. Pat.No. 5,919,769; as well as described by Ikami et al., “Synthetic studieson selectin ligands-inhibitors: Synthesis and inhibitory activity of2-O-fucosyl sulfatides containing 2-branched fatty alkyl residues inplace of ceramide”, Journal of Carbohydrate Chemistry, vol. 17, no. 3,1998 (pp. 453-470) (sulfated 2-O-alpha-L-fucopyranosylbeta-D-galactopyranosides containing 2-branched fatty-alkyl residues inplace of ceramide); Todderud et al., “BMS-190394, a selectin inhibitor,prevents rat cutaneous inflammatory reactions”, J Pharmacol Exp Ther,vol. 282, no. 3, September 1997 (pp. 1298-304) (selectin antagonistBMS-190394, a structural analog of sulfatide). TBC-1269 (available fromTexas Biotechnology Corp., Houston, Tex.) and other mannose derivatives:for example, Dupre et al., “Glycomimetic selectin inhibitors :(alpha-D-mannopyranosyloxy)methylbiphenyls”, Bioorganic & MedicinalChemistry Letters, vol. 6, no. 5, 1996 (pp. 569-572); Lin et al.,“Synthesis of sialyl Lewis x mimetics as selectin inhibitors byenzymatic aldol condensation reactions”, Bioorg Med Chem, vol. 7, no. 3,March 1999 (pp. 425-33) (D-mannosyl phosphate/phosphonate derivativesenzymatically prepared as sialyl Lewis x tetrasaccharide mimics); Koganet al., “Rational design and synthesis of small molecule,non-oligosaccharide selectin inhibitors:(alpha-D-mannopyranosyloxy)biphenyl-substituted carboxylic acids”, J MedChem, vol. 38, no. 26, 22 Dec. 1995 (pp. 4976-84). Leumedins: Endemannet al., “Novel anti-inflammatory compounds induce shedding of L-selectinand block primary capture of neutrophils under flow conditions”, JImmunol 15 May 1997; 158(10):4879-85 (leumedins are small molecules thatinhibit neutrophil movement into inflamed tissues). Di- and tri-valentsmall molecules, mainly 3-carboxyaralkyl-substituted2-α-D-mannopyranosyloxy-phenyl unsubstitued, oxygen-, ornitrogen-substituted alkanes (e.g., oxobutane, piperidine), as describedin U.S. Pat. No. 5,919,768. GSC-150: Wada et al., “Effect of GSC-150, anew synthetic selectin inhibitor, on skin inflammation in mice”,Japanese Journal of Pharmacology, vol. 71, no. Suppl. 1, 1996 (Page302P). Sialyl Lewis x analogs: Kiso et al., “Studies of selectin bindinginhibitors : Synthesis of sialyl-Lewis x and sialyl-Lewis a epitopeanalogs containing 2-acetamido derivative ofN-methyl-1-deoxynojirimycin”, Journal of Carbohydrate Chemistry, vol.15, no. 1, 1996 (pp. 1-14) (synthesis of sialyl-Lewis x (15) andsialyl-Lewis a (17) epitope analogs containing the 2-acetamidoderivative of N-methyl-1-deoxynojirimycin ). Glycolipid sulfatide: Nairet al., “Inhibition of immune complex-induced inflammation by a smallmolecular weight selectin antagonist”, Mediators of Inflammation, vol.3, no. 6, 1994 (pp. 459-463). Triterpene glucosides such asglycyrrhizin: Rao et al., “Glycyrrhetinic acid glycosides are sialylLewis X mimics, and function as selectin inhibitors”, Molecular Biologyof the Cell, vol. 5, no. Suppl., 1994 (pp. 480A); Narasinga et al.,“Sialyl Lewis X Mimics Derived from a Pharmacophore Search Are SelectinInhibitors with Anti-inflammatory Activity”, Journal of BiologicalChemistry, vol. 269, no. 31, 1994 (pp. 19663-19666) (glycyrrhizin, anL-fucose derivative, and a C-fucoside derivative; Subramanian et al.,“Attenuation of renal ischemia-reperfusion injury with selectininhibition in a rabbit model”, Am J Surg, vol. 178, no. 6, December 1999(pp. 573-6). GM-1925: Cornell and Bowyer, “Attenuation of lung injury ina rabbit acid aspiration model using GM-1925, a novel selectininhibitor”, Surgical Forum, vol. 45, 1994 (pp. 107-110). Diisopropylfluorophosphate: Palecanda et al., “Complete inhibition of cross-linkingand activation induced shedding of I selectin by the serine proteaseinhibitor diisopropyl fluorophosphate DPF”, J Immunol, vol. 150, no. 8Part 2, 1993 (page 304A). BR 44-09 and BR 44-096837: Heavner et al.,“Multiple binding site involvement in neutrophil selectin adhesionimplications for design of peptide and carbohydrate inhibitors BIO BR44-09 BR 44-096840”, J Cell Biochem Suppl, no. 17 Part A, 1993 (p. 342);Dalton et al., Inhibition of selectin mediated adhesion in-vivo andin-vitro BIO BR 44-09 BR 44-096837”, J Cell Biochem Suppl, no. 17 PartA, 1993 (p. 342). GMP-140: May et al., “GMP-140 P Selectin inhibitshuman neutrophil activation by lipopolysaccharide analysis by protonmagnetic resonance spectroscopy BIO BA 93-00 BA 93-130631”, BiochemBiophys Res Commun, vol. 183, no. 3, 1992 (pp. 1062-1069).Tetrasaccharides: Ushakova et al., “Inhibitory activity of monomeric andpolymeric selectin ligands”, Vopr Med Khim, vol. 45, no. 5,September-October 1999 (pp. 375-83) (tetrasaccharides SiaLex, SiaLea,HSO₃Lex, their conjugates with polyacrylamide (40 kDa), and severalother monomeric and polymeric substances; all monomeric inhibitors wereabout two orders of magnitude weaker; PAA-conjugates, containing as aligand tyrosine-o-sulfate in addition to one of the above mentionedoligosaccharides, were the most potent synthetic blockers compared withfucoidan, bi-ligand glycoconjugate HSO3Lea-PAA-sTyr); Bertozzi et al.,“Sulfated disaccharide inhibitors of L-selectin: deriving structuralleads from a physiological selectin ligand”, Biochemistry, vol. 34, no.44, 7 Nov. 1995 (pp. 14271-8) (generated a simple small molecule(lactose 6′,6-disulfate) with greater inhibitory potency for L-selectinthan sialyl Lewis x). Panosialins: Shinoda et al., “Panosialins,inhibitors of an alpha1,3-fucosyltransferase Fuc-TVII, suppress theexpression of selectin ligands on U937 cells”, Glycoconj J, vol. 15, no.11, November 1998 (pp. 1079-83). CY-1503: Schmid et al., “Carbohydrateselectin inhibitor CY-1503 reduces neutrophil migration and reperfusioninjury in canine pulmonary allografts”, J Heart Lung Transplant, vol.16, no. 10, October 1997 (pp. 1054-61). Inhibitors of TLRs (toll-likereceptors) and/or other receptors that are sensitive to the LPS-likecompounds associated with acne lesions can be used to ameliorate thesignalling that induces the cytokines TNFα, IL-1β, IL-8, and IL-10, asshown in FIGS. 6 and 8B, and any other related cytokines that areinduced by the P. acnes bacteria. Diglucosamine-based LPS antagonistsinclude E5564 and E5531, described by E. Lien et al., J. Biol. Chem.276(3): 1873-80 (2001), and by T. K. Means et al., J. Immunol., 166(6):4074-82 (2001), inhibit certain TLRs.

Antimicrobials are those commonly used, including those described ordiscussed above. Other antimicrobials can include doxycycline andminocycline and other tetracycline derivatives. Patients who areintolerant to the tetracyclines may benefit from the use oferythromycins such as Erythrocin, Ery-C, E-Mycin; azithromycins such asZithromax; or clarithromycins such as Biaxin, as well as possiblymilbemycins and related compounds. Other possible antibiotics includeaminoglycosides such as amikacin, gentamicin, kanamycin, neomycin,netilmicin, paromomycin, streptomycin, or tobramycin; penicillins suchas penicillin V or amoxicillin; the combination of a penicillin withbeta-lactamase inhibitors, which protect the penicillin from bacterialenzymes that may destroy it before it can do its work, an example ofsuch a combination would be Augmentin; cephalosporins and examples ofthese include cefaclor (Ceclor), cefadroxil (Duricef), cefazolin (Ancef,Kefzol, Zolicef), cefixime, (Suprax), cefoxitin (Mefoxin), cefprozil(Cefzil), ceftazidime (Ceptaz, Fortaz, Tazicef, Tazideme), cefuroxime(Ceftin) and cephalexin (Keflex); fluoroquinolones and examples of theseinclude ciprofloxacin (Cipro), trovafloxacin (Trovan), levofloxacin(Levaquin), norfloxacin (Noroxin), and ofloxacin (Floxin);streptogramins, and sulfonamides including sulfisoxazole (Gantrisin) andthe combination drug sulfamethoxazole and trimethoprim (Bactrim,Cotrim).

Generally, molecules having a molecular weight of less than about 600will pass through the skin, and lipophilic molecules are preferred (or aconjugate having a lipophilic portion). Accordingly, while short chainpeptides are not listed above, those having a low molecular weight and ahigh proportion of lipophilic amino acid residues are likely to beuseful as topical inhibitors of AP-1, NF-KB, elastase, and/or selectin.

The compositions of this invention can be provided in any cosmeticallysuitable form, preferably as a lotion or cream, but also in an ointmentor oil base, as well as a sprayable liquid form (e.g., a spray thatincludes the MMP inhibitor in a base, vehicle, or carrier that dries ina cosmetically acceptable way without the greasy appearance that alotion or ointment would have if applied to the skin).

In addition, the compositions contemplated by this invention can includeone or more compatible cosmetically acceptable adjuvants commonly used,such as colorants, fragrances, emollients, humectants, and the like, aswell as botanicals such as aloe, chamolile, and the like.

When used topically, an inhibitor (of a dermal matrix-degrading enzyme)is used preferably at concentrations of between about 0.05% and about5%, more preferably between 0.1% and 1%.

One enzyme that degrades retinoids and can be inhibited is cytochromeP-450. In the skin, retinoids are converted into retinoic acid (RA) asthe active form. Natural retinoids that function in the skin are alltrans or are metabolized to all trans Retinoic acid (RA; all trans) ismetabolized to inactivation by hydroxylation (via RA 4-hydroxylase) to4-hydroxy-RA, which is then oxidized by a reaction mediated by thecytochrome P-450-dependent monooxygenase system. (S. Kang et al.,“Liarozole Inhibits Human Epidermal Retinoic Acid 4-Hydroxylase Activityand Differentially Augments Human Skin Responses to Retinoic Acid andRetinol In Vivo,” J. Invest. Dermatol., 107:183-187 (August 1996); E. A.Duell et al., “Human Skin Levels of Retinoic Acid and CytochromeP-450-derived 4-Hydroxyretinoic Acid after Topical Application ofRetinoic Acid In Vivo Compared to Concentrations Required to StimulateRetinoic Acid Receptor-mediated Transcription In Vitro,” J. Clin.Invest., Skin Retinoid Levels and Reporter Gene Activity, 90:1269-1274(October 1992); E. A. Deull et al., “Retinoic Acid Isomers Applied toHuman Skin in Vivo Each Induce a 4-Hydroxylase That Inactivates OnlyTrans Retinoic Acid,” J. Invest. Dermatol., 106:316-320 (February 1996).Accordingly, compounds which interfere with the elimination metabolismof all trans RA, the active metabolite of topically applied retinoidssuch as 9-cis RA and 13-cis RA, will beneficially increase the amount ofRA in the skin. Thus, preventing the degradation of natural (all trans)RA in the skin effectively increases its concentration, and so providesthe benefits useful for its treatment of acne.

Retinoids that are likely to be useful for treating rosacea includenatural and synthetic analogs of vitamin A (retinol), vitamin A aldehyde(retinal), vitamin A acid (retinoic acid (RA)), including all-trans,9-cis, and 13-cis retinoic acid), etretinate, and others as described inEP-A2-0 379367, U.S. Pat. No. 4,887,805, and U.S. Pat. No. 4,888,342(the disclosures of which are incorporated herein by reference), and thedissociating retinoids that are specific for AP-1 antagonism (such asthose described by Fanjul, et al. in Nature (1994) 372:104-110). Varioussynthetic retinoids and compounds having retinoid activity are expectedto be useful in this invention, to the extent that they exhibit anti-MMPactivity in vivo, and such are described in various patents assigned ontheir face to Allergan Inc., such as in the following U.S. Pat. Nos.5,514,825; 5,698,700; 5,696,162; 5,688,957; 5,677,451; 5,677,323;5,677,320; 5,675,033; 5,675,024; 5,672,710; 5,688,175; 5,663,367;5,663,357; 5,663,347; 5,648,514; 5,648,503; 5,618,943; 5,618,931;5,618,836; 5,605,915; 5,602,130. Still other compounds described ashaving retinoid activity are described in other U.S. Pat. Nos.5,648,563; 5,648,385; 5,618,839; 5,559,248; 5,616,712; 5,616,597;5,602,135; 5,599,819; 5,556,996; 5,534,516; 5,516,904; 5,498,755;5,470,999; 5,468,879; 5,455,265; 5,451,605; 5,343,173; 5,426,118;5,414,007; 5,407,937; 5,399,586; 5,399,561; 5,391,753, and the like.

Examples of compounds dermatologically acceptable and having or likelyto have inhibitory effects on the CYP-26 (P-450) mediated degradation ofRA and other retinoids include azoles, especially triazoles, including,for example, ketoconazole (U.S. Pat. Nos. 4,144,346 and 4,223,036),fluconazole (U.S. Pat. No. 4,404,216), itraconazole (U.S. Pat. No.4,267,179), liarozole, irtemazole, and the like; compounds related tothese that may also be useful include, for example, diazines such asflucytosine.

It would also be beneficial to use such cytochrome P-450 inhibitors incombination with a reduced amount of retinoid; the P-450 inhibitordecreases the metabolic elimination of the retinoid and so less retinoidis needed to achieve the same result. Still further, analytical methodsare available for determining whether a given compound inhibits thedegradation of RA by applying the compound and testing for changes inCRABP (cytoplasmic retinoic acid binding protein), which will haveincreased levels if the levels of RA are also increased by the topicalapplication of the test compound.

It would also be useful to use inhibitors of CD-14, a patternrecognition protein, part of the innate immune response of humans, thatbinds to LPS-like substances and activates TLRs.

The foregoing description is meant to be illustrative and not limiting.Various changes, modifications, and additions may become apparent to theskilled artisan upon a perusal of this specification, and such are meantto be within the scope and spirit of the invention as defined by theclaims.

1. A method for treating rosacea, comprising: administering acombination of an antimicrobial and an inhibitor of at least one ofNF-KB, AP-1, MMPs, adhesion molecules, TLRs, and CD14.
 2. The method ofclaim 1, wherein the antimicrobial is administered orally and theinhibitor is administered topically.
 3. The method of claim 1, whereinthe antimicrobial is administered topically and the inhibitor isadministered topically.
 4. The method of claim 1, wherein theantimicrobial is a tetracycline or a derivative thereof, an erythromycinor derivative thereof, an azithromycin, a clarithromycin, a milbemycin,an aminoglycoside, a penicillin optionally in combination with abeta-lactamase inhibitor, a cephalosporin, a fluoroquinolone astreptogramin, a sulfonamide, and compatible mixtures thereof.
 5. Amethod for treating rosacea, comprising: administering a combination ofan oral retinoid and an an inhibitor of at least one of NF-KB, AP-1,MMPs, adhesion molecules, TLRs, and CD14.
 6. The method of claim 5,further comprising administering a cytochrome P-450 inhibitor.
 7. Themethod of claim 6, wherein the inhbitor is ketoconazole, fluconazole,itraconazole, liarozole, irtemazole, flucytosine, or a compatiblemixture thereof.
 8. The method of claim 5, further comprising anantimicrobial selected from the group consisting of tetracycline orderivative thereof, an erythromycin or derivative thereof, anazithromycin, a clarithromycin, a milbemycin, an aminoglycoside, apenicillin optionally in combination with a beta-lactamase inhibitor, acephalosporin, a fluoroquinolone a streptogramin, a sulfonamide, andcompatible mixtures thereof.
 9. The method of claim 5, wherein theretinoid is vitamin A (retinol), vitamin A aldehyde (retinal), vitamin Aacid (retinoic acid), etretinate, or a combination thereof.